Cyclosporine a (CSA) is a fungal metabolite developed pharmacologically in the 1970s as a clinical immunosuppressive agent, primarily for control of graft rejection in transplantation. We treated two rhesus infants with CSA in the setting of SIV infection to test the effects of CSA on viral load and disease progression. 3 Possible outcomes of CSA treatment can be measured in a relatively short time in this model 1) no effect on virus load or disease, 2) increased virus load/accelerated disease, and 3) decreased virus load. The 3rd outcome would be considered paradoxical, but there may be direct or indirect anti-viral effects of CSA in vivo. CSA, 4 mg/kg, was diluted in olive oil and administered I.M. as one daily dose to 2 three-month old rhesus inoculated with SIV two weeks earlier. The dosage was adjusted to 5 mg/kg to yield through CSA whole blood levels of 200 - 250 ng/ml. A sensitive measure of total virus load (and the effective host immune response) in the SIV/macaque model of HIV infection is quantitative plasma viremia. In untreated 3 month old macaques, as in juvenile and adult monkeys, plasma viremia is high during acute infection but drops to low or undetectable levels between 2-4 weeks p.I. One of two of the CSA-treated infants had effective reduction of plasma viremia from 2-36 weeks p.I. The plasma virus load in the other infant remained elevated >3 months and then declined. Neither infant developed Simian AIDS before the experiment was terminated at 36 weeks p.I. The route of administration of CSA was problematic. After 3 months of I.M. dosing, myonecrosis at the injection site was diagnosed; we then tried s.q. dosing. After two weeks, subcutaneous nodules were evident. We completed the experiment with oral dosing. This is a difficult procedure in a rhesus infant 36 months of age. We conclude that the effect of csa, at the dosage that we used, on SIV infection and disease was equivocal. Accelerated disease did not occur, but we cannot distinguish outcomes 1 and 3 defined above.